Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation

Mutations in cancer-causing genes induce changes in gene expression programs critical for malignant cell transformation. Publicly available gene expression profiles produced by modulating the expression of distinct cancer genes may therefore represent a rich resource for the identification of gene signatures common to seemingly unrelated cancer genes. We combined automatic retrieval with manual validation to obtain a data set of high-quality gene microarray profiles. This data set was used to create logical models of the signaling events underlying the observed expression changes produced by various cancer genes and allowed to uncover unknown and verifiable interactions. Data clustering revealed novel sets of gene expression profiles commonly regulated by distinct cancer genes. Our method allows retrieval of significant new information and testable hypotheses from a pool of deposited cancer gene expression experiments that are otherwise not apparent or appear insignificant from single measurements. The complete results are available through a web-application at http://biodata.ethz.ch/cgi-bin/geologic .

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P–446 Controlled ovarian stimulation protocols for oocyte vitrification induce differential gene expression profiles in primary tumours of breast cancer

Human Reproduction ◽

10.1093/humrep/deab130.445 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

M J Soriano ◽

L M De. Castillo ◽

J Martínez ◽

S Herraiz ◽

C Díaz-García

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Proliferation ◽

Ovarian Stimulation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Malignant Cell ◽

Oocyte Vitrification ◽

Over Expression ◽

Differential Gene

Abstract Study question Could controlled ovarian stimulation (COS) protocols used in fertility preservation (FP) impact on malignant cell proliferation and tumour molecular profiling of breast cancer (BC) patients? Summary answer Letrozole supplementation during ovarian stimulation for oocyte vitrification could be considered as a safe procedure in estrogen-dependent BC patients undergoing FP. What is known already High estradiol levels associated to COS could promote changes in gene expression in estrogen-positive BC tumors. Estradiol levels reached during the ovarian stimulation could aggressively promote malignant cell proliferation and cell migration to adjacent organs. Aromatase inhibitors such as letrozole, are added to standard stimulation protocols to avoid this undesirable potential side effect. Despite the reassuring clinical results achieved by using letrozole for FP in BC patients, there is still a lack of evidence regarding its impact on malignant cell behaviour. For this reason, specific molecular studies to properly evaluate safety of letrozole in this specific population are still required. Study design, size, duration Experimental in vivo study. Thirty 5-week-old Nude-nu female mice were divided into three different groups: BC (n = 10), BC and FSH stimulation (BC-FSH, n = 10), or BC and letrozole stimulation (BC-LTZ, n = 10). BC was considered the control group, whereas BC-FSH and BC-LTZ represented distinct COS protocols. Hormone-dependent BC was induced in all mice. Animals were followed-up for 5 months and then euthanized to collect kidney, ovary, spleen, and liver tissues for gene expression and immunohistochemistry (IHC) analysis. Participants/materials, setting, methods One million of human MCF–7 BC cells were injected into the mouse left kidney capsule. Two days after xenograft, COS was induced by 10IU FSH or 1mg/ml letrozole + 10IU FSH, followed by ovarian triggering with 10IU hCG at 48h. Human BC RT2 Profiler PCR Arrays were performed to evaluate the impact of COS on tumour behaviour. BC biomarkers (Ki67, Erα, PR and HER–2) were also analyzed by IHC to validate gene expression results. Main results and the role of chance The differential gene expression was firstly assessed in kidney samples, as they represent the xenograft site, and different expression profiles were obtained depending on the COS protocol used. The BC-FSH group showed a global over-expression pattern of all genes of the array when compared to BC and BC-LTZ. Further gene ontology analysis revealed that cellular process, biological regulation, metabolic process, and proteases were the most over-represented biological terms, with a 20.5-fold over-expression for MMP2 compared to the other groups. On the other hand, BC-LTZ mice presented gene expression profiles similar to that of controls. When other tissues were analysed to detect malignant cell presence, our results revealed a significant up-regulation of matrix-proteases, cell cycle and proliferation related-genes, in liver samples from the BC-FSH group, but no amplification of any of the studied genes was detected in ovarian tissue or spleen. IHC findings confirmed the presence of human BC cells in 100% of samples from kidney tissue and in 30% of samples from liver tissue in the BC-FSH group. No human cells were detected by IHC in the BC and BC-LTZ groups. Limitations, reasons for caution Since this is an animal model of estrogen-dependent BC induced through a cell line, further validation with human tumour breast cancer samples would be required. Wider implications of the findings: Adjuvant letrozole in COS protocols prevents BC cell migration. The present study suggests that this protective effect could be mediated by interfering ER-pathway downstream genes involved in cell proliferation and matrix digestion. Altogether, letrozole could safely be used as a supplement during COS procedures for oocyte vitrification in BC women. Trial registration number Not applicable

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Mechanisms of YAP/TAZ transcriptional control

Cell Stress ◽

10.15698/cst2021.11.258 ◽

2021 ◽

Vol 5 (11) ◽

pp. 167-172

Author(s):

Giusy Battilana ◽

Francesca Zanconato ◽

Stefano Piccolo

Keyword(s):

Gene Expression ◽

Regulatory Networks ◽

Transcriptional Control ◽

Cell Transformation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Regulatory Elements ◽

Specific Gene ◽

Chromatin Regulators ◽

Small Set

Dysregulated gene expression is intrinsic to cell transformation, tumorigenesis and metastasis. Cancer-specific gene-expression profiles stem from gene regulatory networks fueled by genetic and epigenetic defects, and by abnormal signals of the tumor microenvironment. These oncogenic signals ultimately engage the transcriptional machinery on the cis -regulatory elements of a host of effector genes, through recruitment of transcription factors (TFs), co-activators and chromatin regulators. That said, whether gene -expression in cancer cells is the chaotic product of myriad regulations or rather a relatively ordered process orchestrated by few TFs (master regulators) has long remained enigmatic. Recent work on the YAP/TAZ co-activators has been instrumental to break new ground into this outstanding issue, revealing that tumor cells hijack growth programs that are active during development and regeneration through engagement of a small set of interconnected TFs and their nuclear partners.

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Kaposi’s Sarcoma-Associated Virus Governs Gene Expression Profiles Toward B Cell Transformation

Herpesviridae - A Look Into This Unique Family of Viruses ◽

10.5772/23250 ◽

2012 ◽

Author(s):

Keiji Ueda ◽

Emi Ito ◽

Masato Karayama ◽

Eriko Ohsaki ◽

Kazushi Nakano ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Kaposi's Sarcoma ◽

Cell Transformation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Kaposi’S Sarcoma

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An Overview of the Epigenetic Modifications of Gene Expression in Tumorigenesis

Research in Molecular Medicine ◽

10.18502/rmm.v6i3.4606 ◽

2019 ◽

Author(s):

Leili Sadeghi Amiri ◽

Ali Barzegar ◽

Alireza Rafiei ◽

Omolbanin Amjadi

Keyword(s):

Gene Expression ◽

Cell Transformation ◽

Regulation Of Gene Expression ◽

Malignant Cell ◽

Chromatin Modifications ◽

Chromatin Compaction ◽

Cellular Processes ◽

The Past ◽

Development And Differentiation ◽

Malignant Cell Transformation

The five leading causes of cancer-related deaths are lung (1,760,000 deaths), colorectal (862,000 deaths), stomach (783,000 deaths), liver (782,000 deaths), and breast (627,000 deaths) cancers. Epigenetic changes can alter chromatin compaction, leading to the regulation of gene expression without changing the primary DNA sequence. Epigenetic mechanisms are normally involved in cellular processes such as genomic stability, chromosome X inactivation, and embryonic development and differentiation. Similar to other types of chromatin modifications, DNA methylation has been verified to affect the expression of various genes. Any impairment in these mechanisms alters the regulation of gene expression and can contribute to malignant cell transformation. Over the past few years, extensive innovations within the field of epigenetics have encouraged its application as a major strategy for the treatment of important diseases such as cancer.

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ETV6 Is An Early T-Cell Progenitor (ETP) Specific Tumor Suppressor Gene in Adult T-ALL

Blood ◽

10.1182/blood.v118.21.406.406 ◽

2011 ◽

Vol 118 (21) ◽

pp. 406-406 ◽

Cited By ~ 1

Author(s):

Pieter Van Vlierberghe ◽

Alberto Ambesi ◽

Isaura Rigo ◽

Elisabeth Paietta ◽

Janis Racevskis ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Tumor Suppressor ◽

Mutation Analysis ◽

Splice Site ◽

Cell Transformation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Genetic Alterations ◽

Gene Set Enrichment Analysis

Abstract Abstract 406 T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease in which genetic lesions coordinately affect cell proliferation, differentiation and survival of thymocytes. Although pediatric T-ALL has been extensively studied on the genomic level during the last decade, large scale genomic studies in adult T-ALL are sparse. Importantly, significant differences in treatment outcome are present between pediatric and adult T-ALL. Here we performed integrative analysis of gene expression, copy number alterations and mutation analysis on 58 adult T-ALL samples treated in the Eastern Cooperative Oncology Group (ECOG) E2993 protocol. Unsupervised and consensus clustering of microarray gene expression data in this series revealed the presence of 2 stable gene expression clusters resembling immature/ETP (n=30) and typical (n=28) T-ALL gene signatures. Indeed, gene set enrichment analysis (GSEA) confirmed that our ETP/immature adult T-ALL signature closely resembled the previously published ETP profiles. In this adult patient cohort, the immature/ETP patient samples were associated with poor outcome (5 year OS 36% for ETP and 58% for non ETP TALL, P=0.088). Additional supervised analyses revealed differential expression of ERAP2, a gene involved in the processing of MHC peptides, between early relapse and long time survivor adult T-ALL patients. Consistently low ERAP2 expression was associated poor prognosis in adult T-ALL (OS 26%, 36% and 78% for 1st 2nd and 3rd terciles respectively, P=0.016). In addition, absence of TCR gamma deletion (p=0.013) as well as the absence of biallelic CDKN2A/CDKN2B deletion (p=0.009) were shown to be poor prognostic markers in adult T-ALL. To gain additional insight in the biology of adult ETP T-ALL, we performed GSEA analysis using the immature/ETP gene expression profiles. This analysis revealed that the adult ETP T-ALL signature is more closely related to acute myeloid leukemia (AML) profiles as compared to ALL signatures. Given this, we hypothesized that myeloid specific genetic alterations might be uniquely present in ETP adult T-ALL. Mutation analysis of AML oncogenes and tumor suppressor genes revealed the presence of myeloid mutations targeting IDH1, IDH2, DNMT3A, FLT3 and N-RAS in 13/30 (43%) of adult ETP T-ALL cases, whereas only 1/28 (3.5%) typical adult T-ALL showed a mutation in N-RAS. Although these ETP adult T-ALL samples seem to have myeloid properties, they still retain T-lymphoid characteristics including activational NOTCH1 mutations in 12/30 (40%) of ETP adult T-ALLs. Of note, the myeloid specific genetic alterations were preferentially present in NOTCH1 wild type ETP adult T-ALL samples. Next, we used a systems biology approach to identify master regulators that might be able to drive the ETP signature identified in adult T-ALL. For this, we interrogated a T-ALL interactome that was constructed from gene expression profiles of 228 human T-ALL samples. This master regulator analysis identified MN1 as the key transcription factor driving the ETP signature. The MN1 gene was initially identified as fusion partner of TEL (ETV6) in patients with AML. Notably, MN1-TEL expression in multipotent progenitors induces both AML and T-ALL and mutation analysis of ETV6 in adult T-ALL revealed the presence of 10 ETV6 mutants (9 frameshift and 1 splice site mutation) in adult T-ALL. Analysis of bone marrow remission genomic DNA confirmed the somatic origin of ETV6 mutations (3 frameshift and 1 splice site) in each of the 4 patient samples with available material. Most notably, ETV6 mutations were exclusively present in the ETP subtype of adult T-ALL. In addition, 8/10 (80%) of ETV6 mutant ETP T-ALL cases were characterized mutations in NOTCH1, suggesting a specific interaction between the oncogenic NOTCH1 programs and the mutational loss of ETV6 in early T-cell transformation. In conclusion, our integrative genomic analyses in adult T-ALL unraveled a high prevalence of immature/early T-cell progenitor (ETP) T-ALLs, associates the pathogenesis of ETP-TALL with myeloid mutations and identifies ETV6 truncating alleles as the first ETP specific gene mutation that strongly interact with NOTCH1 in T-cell transformation. Disclosures: No relevant conflicts of interest to declare.

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